检索问题
目前胶束制剂进入到临床试验阶段的有哪些？进展如何？
胶束制剂作为纳米载体在癌症治疗、脑部疾病治疗以及眼部药物递送等领域显示出巨大的潜力，并且多种胶束制剂已经进入到临床试验阶段，甚至有部分已获得批准。这些制剂的进展各不相同，有的处于早期临床研究，有的则已进入后期试验，甚至成功上市。
胶束制剂的优势与应用背景： 胶束是由两亲性嵌段共聚物自组装形成的纳米级载体，通常由疏水核心和亲水外壳组成。这种结构使其能够有效封装疏水性药物，增加药物的溶解度和稳定性。胶束的纳米尺寸（通常在5-100 nm之间）以及聚乙二醇（PEG）等亲水外壳使其能够逃避网状内皮系统的非特异性捕获，从而实现长循环时间。它们还能通过增强渗透和保留（EPR）效应选择性地在实体瘤中积累，这是由于肿瘤组织血管渗漏和淋巴引流受损的特点所致。EPR效应使得胶束在肿瘤部位实现更高的药物浓度，同时减少对正常组织的毒副作用，从而提高治疗效果并降低不良反应。
除了被动靶向外，胶束还可以进行修饰以实现主动靶向和刺激响应性，进一步提高药物向目标部位的递送效率和受控释放。胶束在多药联合递送方面也表现出潜力，能够同时递送多种抗癌药物或将遗传物质与化疗药物结合，以实现协同治疗效果。
癌症治疗领域的胶束制剂进展：
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紫杉醇（Paclitaxel）胶束： 紫杉醇是一种广泛使用的抗癌药物，但其标准制剂（如Taxol）中的溶剂（如Cremophor EL）常引起严重的副作用，如过敏反应。纳米技术的发展为解决这些问题提供了机会，其中胶束制剂被广泛应用于紫杉醇的递送，以提高其疗效、安全性和药代动力学特性。
- Genexol-PM： 这是紫杉醇的一种聚合物胶束制剂，已获得FDA批准用于乳腺癌患者的治疗。它在许多实体瘤中显示出强大的抗肿瘤活性，并且与其他纳米载体（如聚合物纳米颗粒Abraxane和脂质体Lipusu）一起，是目前市场上紫杉醇三种不同的肠道递送纳米平台之一。
- Nanoxel和Paclical： 这也是紫杉醇的聚合物胶束制剂，目前已上市，并在临床上用于癌症治疗。
- NK105： 这是一种紫杉醇包覆的胶束，目前正在进行III期临床试验。临床前和临床研究表明，NK105能够通过EPR效应在肿瘤中有效积累，并显示出良好的抗肿瘤活性。
- ZSYY001 (PM-paclitaxel)： 这是一种新型聚合物胶束紫杉醇，旨在避免与Cremophor EL相关的副作用。临床前研究显示，ZSYY001在A549、MDA-MB-231和SKOV3异种移植肿瘤模型中显著抑制肿瘤生长，且不引起体重减轻。在I期临床研究中，ZSYY001被证明是安全且耐受性良好，未观察到急性超敏反应，最常见的毒性是贫血和脱发。该研究的剂量逐步递增至390 mg/m²，未达到最大耐受剂量。在18名可评估肿瘤反应的患者中，有两例部分缓解（11.11%）和七例病情稳定（38.89%），其中五名患者曾接受过紫杉醇化疗。这些结果表明ZSYY001具有良好的抗肿瘤活性和安全性，有潜力成为一种有前景的治疗方法。
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顺铂（Cisplatin）胶束：
- NC-6004： 这是一种顺铂包覆的胶束，目前处于临床评估阶段。顺铂作为一种广泛使用的化疗药物，其毒副作用较大。将顺铂封装在胶束中可以提高其在肿瘤部位的靶向性，从而降低全身毒性并提高疗效。
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表柔比星（Epirubicin）胶束：
- NC-6300： 这是一种表柔比星包覆的胶束，也正在进行临床评估。与顺铂类似，表柔比星的胶束化旨在改善其治疗指数，减少不良反应。
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Spicamycin衍生物 KRN5500 胶束（KRN/m）： KRN5500是一种通过抑制蛋白质合成发挥抗肿瘤活性的spicamycin衍生物，对人类肿瘤异种移植模型显示出显著疗效。然而，其I期临床试验中出现了严重的药物毒性，包括4级肺部疾病，部分原因是其溶解所需的有机溶剂和化学物质。为了克服这些副作用，研究人员将KRN5500封装到聚合物胶束中（KRN/m）。动物模型研究表明，KRN/m在保留KRN5500强大抗肿瘤活性的同时，显著降低了肺部毒性。这些结果支持KRN/m进入I期临床试验。
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其他抗癌药物胶束： 除了上述药物，多种其他抗癌药物的胶束制剂也处于临床前和临床评估阶段。例如，胶束已被证明在结直肠癌（CRC）治疗中具有潜力，能够提高化疗药物的药代动力学特性，增强其安全性和抗癌功效。胶束还可以递送抗癌遗传物质，如siRNA和miRNA，这为癌症基因治疗提供了新途径，特别是在化疗和放疗耐药的情况下。目前，针对RNA干扰的胶束样纳米颗粒正在进行体外、体内和临床研究。
脑部疾病治疗领域的胶束制剂进展： 聚合物胶束在改善药物向大脑递送方面开辟了新途径，特别是因为它们的小尺寸、长循环时间、良好的稳定性和靶向性。它们被用于治疗多种脑部疾病，包括胶质母细胞瘤、偏头痛、阿尔茨海默病、帕金森病等。然而，由于大多数药物无法穿过血脑屏障，胶束在脑部靶向中的应用仍未得到充分利用。尽管如此，科学家们正在不断努力寻找有效的解决方案，并有相关的专利和临床试验正在进行中，以评估胶束在脑部疾病治疗中的潜在未来应用。
眼部药物递送领域的胶束制剂进展： 传统的眼部局部给药面临诸多挑战，例如角膜复杂结构限制药物吸收、眼部吸收细胞的药物代谢能力以及泪液的冲洗作用。聚合物胶束因其能够溶解疏水性药物、无刺激性、纳米级直径以及水溶液透明不影响视力等优势，在眼部药物递送方面备受关注。它们还可能增加药物在吸收部位的释放和停留时间。
- Cequa： Sun Pharmaceuticals公司生产的Cequa是美国食品药品监督管理局（FDA）批准的首个用于临床的纳米胶束制剂，用于眼部给药。这一成功案例表明了胶束系统在眼科领域的巨大潜力。
临床试验概况与挑战： 美国FDA要求所有药物在合法销售前必须经过FDA审批流程，包括临床试验。目前，有77种纳米药物产品正在进行临床试验，其中约40%的试验在2014或2015年开始。虽然FDA批准的纳米药物主要集中在聚合物、脂质体和纳米晶体配方，但胶束、蛋白质基纳米颗粒以及各种无机和金属颗粒的开发趋势也在临床试验中显现。
尽管胶束制剂在临床前研究中取得了显著的成功，并有多个制剂进入临床试验，但将胶束转化为治疗环境仍然面临挑战。这些挑战包括材料选择、制剂策略、稳定性和生物安全性优化，以及如何更好地理解纳米结构及其行为。研究人员、工业界和监管机构面临的关键挑战是如何对新材料进行分类，以及在产品上市前需要进行哪些额外的检测（例如安全性评价和毒性测试）。
总结来说，聚合物胶束作为一种多功能的药物递送系统，在癌症治疗、脑部疾病和眼部疾病等多个领域展现出巨大的应用前景。多种胶束制剂已成功进入临床试验，有些甚至获得了市场批准，这表明了其在解决传统药物递送挑战方面的有效性和潜力。未来的研究将继续致力于开发更具靶向性、多功能性和智能响应性的胶束，以实现更安全、更有效的临床应用。
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Zaynab Fatfat, Maamoun Fatfat, Hala Gali-Muhtasib
Despite the significant progress in cancer therapy, colorectal cancer (CRC) remains one of the most fatal malignancies worldwide. Chemotherapy is currently the mainstay therapeutic modality adopted for CRC treatment. However, the long-term effectiveness of chemotherapeutic drugs has been hampered by their low bioavailability, non-selective tumor targeting mechanisms, non-specific biodistribution associated with low drug concentrations at the tumor site and undesirable side effects. Over the last decade, there has been increasing interest in using nanotechnology-based drug delivery systems to circumvent these limitations. Various nanoparticles have been developed for delivering chemotherapeutic drugs among which polymeric micelles are attractive candidates. Polymeric micelles are biocompatible nanocarriers that can bypass the biological barriers and preferentially accumulate in tumors the enhanced permeability and retention effect. They can be easily engineered with stimuli-responsive and tumor targeting moieties to further ensure their selective uptake by cancer cells and controlled drug release at the desirable tumor site. They have been shown to effectively improve the pharmacokinetic properties of chemotherapeutic drugs and enhance their safety profile and anticancer efficacy in different types of cancer. Given that combination therapy is the new strategy implemented in cancer therapy, polymeric micelles are suitable for multidrug delivery and allow drugs to act concurrently at the action site to achieve synergistic therapeutic outcomes. They also allow the delivery of anticancer genetic material along with chemotherapy drugs offering a novel approach for CRC therapy. Here, we highlight the properties of polymeric micelles that make them promising drug delivery systems for CRC treatment. We also review their application in CRC chemotherapy and gene therapy as well as in combination cancer chemotherapy.
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Ankita Tiwari, Shivani Saraf, Ankit Jain, et al.
Colorectal cancer (CRC) is the third most common cancer existing across the globe. It begins with the formation of polyps leading to the development of metastasis, especially in advanced stage patients, who necessitate intensive chemotherapy that usually results in a poor response and high morbidity owing to multidrug resistance and severe untoward effects to the non-cancerous cells. Advancements in the targeted drug delivery permit the targeting of tumor cells without affecting the non-tumor cells. Various nanocarriers such as liposomes, polymeric nanoparticles, carbon nanotubes, micelles, and nanogels, etc. are being developed and explored for effective delivery of cytotoxic drugs to the target site thereby enhancing the drug distribution and bioavailability, simultaneously subduing the side effects. Moreover, immunotherapy for CRC is being explored for last few decades. Few clinical trials have even potentially benefited patients suffering from CRC, still immunotherapy persists merely an experimental alternative. Assessment of the ongoing and completed trials is to be warranted for effective treatment of CRC. Scientists are paying efforts to develop novel carrier systems that may enhance the targeting potential of low therapeutic index chemo- and immune-therapeutics. Several preclinical studies have revealed the superior efficacy of nanotherapy in CRC as compared to conventional approaches. Clinical trials are being recruited to ascertain the safety and efficacy of CRC therapies. The present review discourses in a nutshell the molecular interventions including the genetics, signaling pathways involved in CRC, and advances in various strategies explored for the treatment of CRC with a special emphasis on nanocarriers based drug targeting.
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Nobuhiro Nishiyama, Yasuhiro Matsumura, Kazunori Kataoka
In relation to recent advances in nanobiotechnologies, cancer-targeted therapy using nano-scaled drug carriers (nanocarriers) has been attracting enormous attention with success in clinical studies. Polymeric micelles, core-shell-type nanoparticles formed through the self-assembly of block copolymers, are one of the most promising nanocarrier, because their critical features such as size, stability, and drug incorporation efficiency and release rate can be modulated by designing the constituent block copolymers. The utilities of polymeric micelles have been reported not only in experimental tumor models in mice but also in clinical studies. In this article, we aim to explain the rationale of designing polymeric micelles for targeting intractable cancers such as pancreatic cancer, glioblastoma, and metastases. Also, we review recent progress in clinical studies on polymeric micelles incorporating anticancer drugs. In addition, we introduce the next generation of polymeric micelles as the platform integrated with smart functionalities such as targetability, environmental sensitivity, and imaging properties. Thus, polymeric micelles can realize safe and effective cancer therapy, and offer tailor-made medicines for individual patients.
17Preclinical Development and Phase I Study of ZSYY001, a Polymeric Micellar Paclitaxel for Advanced Solid Tumor.PubMed
Ge Gao, Pei Shu, Youzhen Tan, et al.
PURPOSE: A novel paclitaxel delivery system has the potential to avoid the side effects associated with Cremophor EL and thus enhance therapeutic efficacy. Here, we report the results of a preclinical and phase I clinical study investigating ZSYY001, a nanoparticle formulation of polymeric micellar paclitaxel (PM-paclitaxel). METHODS: In preclinical studies, A549, MDA-MB-231, and SKOV3 xenograft tumor models were developed. Various concentrations of ZSYY001 were administered, and tumor growth and body weight were measured. Sprague-Dawley (SD) rats and Beagle dogs were used to evaluate the toxicity. In the phase I study, a dose-escalation study using a 3 + 3 design was conducted in patients with solid tumors. The PM-paclitaxel dose was escalated from 175 mg/m to 390 mg/m. PM-paclitaxel was intravenously administered over 3 h every 21 days without any premedication. This study was registered with number CTR20210347. RESULTS: Preclinical studies showed that ZSYY001 significantly inhibited tumor growth without causing weight loss. In the phase I study, all patients were evaluable for toxicity and pharmacokinetic analysis, and 18 patients were evaluable for tumor response. Acute hypersensitivity reactions were not observed. Anemia and hair loss were the most common toxicities. Dose-limiting toxicity events were not observed at any dose levels. Dose escalation to 390 mg/m did not identify a maximum-tolerated dose. There were two partial responses (11.11%) and seven cases of stable disease (38.89%) among the 18 patients, five of whom had prior exposure to paclitaxel chemotherapy. The paclitaxel area under the curve and peak paclitaxel concentration suggest that PM-paclitaxel does not exhibit linear pharmacokinetics. CONCLUSIONS: ZSYY001 was safe and well tolerated without additional toxicity and exhibited desirable antitumor activity, making it a promising treatment. TRIAL REGISTRATION: CTR20210347.
18Role of Polymeric Micelles in Ocular Drug Delivery: An Overview of Decades of Research.PubMed
Ziyad Binkhathlan, Raisuddin Ali, Abdullah H Alomrani, et al.
Local drug delivery to the eye through conventional means has faced many challenges due to three essential barriers: (a) the complex structure of the cornea limiting drug absorption, (b) the capacity of ocular absorptive cells in drug metabolism, and (c) the washing effect of eye tears. Polymeric micelles (PMs) have been the focus of much interest for ocular drug delivery due to several advantages they provide for this application, including the capacity for the solubilization of hydrophobic drugs, nonirritability, nanoscopic diameter, and the clarity of their aqueous solution not interfering with vision. The potential to increase the release and residence time of incorporated medication at the site of absorption is also a bonus advantage for these delivery systems. This Review covers research conducted on single or mixed micelles prepared from small amphiphilic molecules, copolymers (diblock, triblock, and graft), and gel systems containing micelles. The purpose of this review is to provide an update on the status of micellar ocular delivery systems for different indications, with a focus on preclinical and clinical drug development. In this context, we are discussing the anatomy of the eye, various ocular barriers, different micellar formulations, and their benefits in ocular drug delivery, as well as the role of PMs in the management of ocular diseases both in preclinical models and in clinic. The encouraging preclinical effectiveness findings from experiments conducted in both laboratory settings and live animals have paved the way for the advancement of micellar systems in clinical trials for ocular administration and the first nanomicallar formulation approved for clinical use by the United States Food and Drug Administration (marketed as Cequa by Sun Pharmaceuticals).
19Polymeric micelles in anticancer therapy: targeting, imaging and triggered release.PubMed
Chris Oerlemans, Wouter Bult, Mariska Bos, et al.
Micelles are colloidal particles with a size around 5-100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of which Genexol-PM has been FDA approved for use in patients with breast cancer. Micelle-based drug delivery, however, can be improved in different ways. Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies. Moreover, pH-, thermo-, ultrasound-, or light-sensitive block copolymers allow for controlled micelle dissociation and triggered drug release. The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a 'magic bullet' a major step forward.